Amine-containing neurons are found in relatively small numbers in specific nuclei deep within the brainstem in essentially all vertebrate species, including humans. Despite their limited numbers, amine effects on behavior are profound as their neuronal processes ramify widely throughout the nervous system. Dysfunctioning of amine neuron systems has been implicated in the pathology of many psychiatric and neurological diseases. Included are motor system disorders like Parkinson's Disease in which subsets of the dopamine neurons selectively die, and psychiatric disorders including mood disorders, schizophrenia, attention-deficit hyperactivity disorder and drug abuse in which the amines dopamine, serotonin and norepinephrine all have been directly implicated. Arousal, reward, learning and memory, risk taking behavior, aggression and stress related behavioral and physiological responses are some of the multitude of essential human behaviors in which amine neurons have been suggested to play key roles. With likely roles in so many central aspects of human behavior, it is no wonder that a huge literature has grown up on amine neuron systems and how they function. Originally thought to be fairly homogeneous populations of neurons found in selective CNS nuclear regions, continuing study has revealed that these systems instead are very heterogeneous populations of neurons in terms of their function and their morphology, even within single brainstem nuclei. The most challenging part of understanding these systems now is to understand how they coordinate and/or organize the many behavioral processes they seem concerned with. A difficulty in addressing such questions in higher vertebrate nervous systems is that even though the numbers of amine neurons involved are relatively small compared to the total numbers of neurons in the brain, it is highly unlikely that one will find the same neuron more than once to explore its function in detail. Recently developed methods in other model systems, however, allow targeting and manipulation of single identified amine neurons. These experimental approaches are the farthest advanced in fruit flies (Drosophila melanogaster) where powerful genetic methods allow identification and manipulation of single neurons concerned with behavior. As in vertebrate systems, amines have been shown to be intimately involved in many essential aspects of behavior in fruit flies, including motivation and reward, locomotion and feeding, learning and memory, and courtship and aggression. The studies proposed here have three Specific Aims concerned with bringing the study of how amine neurons work in fruit flies to an identified single neuron level. They are: Aim 1: Use of a combinatorial genetic approach to identify small subsets of amine neurons; Aim 2: The behavioral consequences of altering the functional properties of single amine-containing neurons; and Aim 3: Analysis of the circuitry associated with single amine neurons. Studies at these levels of detail are not possible in other species at the present time. PUBLIC HEALTH RELEVANCE: Amine neuron systems of the brain are centrally involved in complex behavioral traits including psychiatric and motor diseases, drug addiction, motivation and reward, stress-related disorders, aggression and sleep. Using a model system, this application asks how single amine neurons function in generating such traits.